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`IPR2016-00710
`Patent Owners’ Response
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`Adam R. Brausa
`Reg. No. 60,287
`Daralyn J. Durie
`Pro Hac Vice
`Durie Tangri LLP
`217 Leidesdorff Street
`San Francisco, CA 94111
`
`
`Michael R. Fleming
`Reg. No. 67,933
`David I. Gindler
`Pro Hac Vice
`Joseph M. Lipner
`Pro Hac Vice
`Irell & Manella LLP
`1800 Avenue of the
`Stars, Suite 900
`Los Angeles, CA
`90067
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`Filed on behalf of Patent Owners Genentech, Inc. and City of Hope by:
`
`David L. Cavanaugh
`Reg. No. 36,476
`Owen K. Allen
`Reg. No. 71,118
`Heather M. Petruzzi
`Reg. No. 71,270
`Robert J. Gunther, Jr.
`Pro Hac Vice
`Wilmer Cutler Pickering
`Hale and Dorr LLP
`1875 Pennsylvania Ave., NW
`Washington, DC 20006
`
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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`____________________________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`____________________________________________
`
`MYLAN PHARMACEUTICALS, INC.,
`Petitioner,
`
`v.
`
`GENENTECH, INC. AND CITY OF HOPE,
`Patent Owners.
`____________________________________________
`
`Case IPR2016-00710
`Patent 6,331,415
`____________________________________________
`
`PATENT OWNERS’ RESPONSE
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`I. 
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`II. 
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`A. 
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`B. 
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`C. 
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` IPR2016-00710
`Patent Owners’ Response
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`TABLE OF CONTENTS
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` Page
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`INTRODUCTION ........................................................................................... 1 
`
`TECHNOLOGY BACKGROUND ................................................................. 6 
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`Proteins Vary In Size And Complexity. ..................................................... 6 
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`Prior Art Antibody Production Techniques ............................................... 9 
`
`By April 1983, Recombinant Techniques Were Not Well
`Understood And Had Only Been Used To Make Simple Proteins. ......... 10 
`
`D.  As Of April 1983, Leading Scientists Were Uncertain Whether It
`Was Possible To Make Antibodies Recombinantly. ................................ 13 
`
`III.  THE ’415 PATENT ....................................................................................... 18 
`
`A. 
`
`B. 
`
`The Invention ............................................................................................ 18 
`
`Industry Recognition ................................................................................ 19 
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`IV.  PROCEDURAL HISTORY .......................................................................... 20 
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`V. 
`
`PERSON OF ORDINARY SKILL ............................................................... 23 
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`VI.  CLAIM CONSTRUCTION .......................................................................... 23 
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`VII.  ARGUMENT ................................................................................................. 23 
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`A.  Ground 1: Claims 1, 3-4, 11-12, 14, 19, And 33 Would Not Have
`Been Obvious Over Bujard In View Of Riggs & Itakura. ....................... 23 
`
`1. 
`
`Bujard does not suggest co-expression in a single host cell to
`produce antibodies. .............................................................................. 24 
`
`a) 
`
`Summary of Bujard ........................................................................ 24 
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`c) 
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`Bujard does not disclose any process for producing
`antibodies. ...................................................................................... 25 
`
`Bujard does not disclose co-expressing multiple genes of
`interest in a single host cell. ........................................................... 30 
`
`(i)    Bujard’s “multimers” do not refer to a multi-chain
`protein, such as an antibody. ..................................................... 30 
`
`(ii)  
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`“One or more structural genes” includes selectable
`markers, and is not a disclosure of the heavy and light
`chains of an antibody. ............................................................... 33 
`
`(iii) 
`
`“A plurality of translational stop codons” efficiently
`terminates translation of a single gene. ..................................... 36 
`
`(iv)  There was no “prevailing mindset” that multiple
`eukaryotic genes could be co-expressed in a single host
`cell. ............................................................................................ 37 
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`d)  Mylan’s remaining arguments about Bujard lack merit. ............... 39 
`
`(i)   
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`(ii)  
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`“One or more hosts for gene expression” ................................. 39 
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`“Prepared as a single unit or as individual subunits” ............... 40 
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`2. 
`
`Riggs & Itakura does not disclose the co-expression in a single
`host cell limitation absent from Bujard. .............................................. 41 
`
`a) 
`
`b) 
`
`c) 
`
`Summary of Riggs & Itakura ......................................................... 42 
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`A person of ordinary skill would have had no reason to
`combine Bujard with Riggs & Itakura. .......................................... 43 
`
`Bujard combined with Riggs & Itakura would have led to a
`two host cell approach, not the single host cell invention of
`the challenged claims. .................................................................... 44 
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`3. 
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`The ’415 invention was not obvious to try. ......................................... 47 
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`4. 
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`A person of ordinary skill would not have had a reasonable
`expectation of success in extending Riggs & Itakura’s
`techniques to antibodies. ..................................................................... 49 
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`B. 
`
`Ground 2: Claims 1, 2, 18, 20, And 33 Would Not Have Been
`Obvious Over Bujard In View Of Southern. ............................................ 52 
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`1. 
`
`2. 
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`3. 
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`4. 
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`Bujard does not suggest co-expression in a single host cell to
`produce antibodies. .............................................................................. 52 
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`Southern does not disclose or suggest the “single host cell” or
`the two vector limitations absent from Bujard. ................................... 53 
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`a) 
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`b) 
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`c) 
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`d) 
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`Summary of Southern .................................................................... 54 
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`A person of ordinary skill would not have combined Bujard
`with Southern. ................................................................................ 55 
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`Southern does not disclose including multiple “genes of
`interest” in separate vectors. .......................................................... 56 
`
`Other publications confirm that a skilled artisan would not
`have applied Southern to express heavy and light chains
`from separate vectors in the same host cell. .................................. 60 
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`A skilled artisan would have had no reasonable expectation of
`success combining Bujard with Southern. .......................................... 61 
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`Southern cannot invalidate claims 1, 2, and 33. .................................. 62 
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`C. 
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`Objective Indicia Confirm The Patentability Of The Challenged
`Claims. ...................................................................................................... 62 
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`VIII.  CONCLUSION .............................................................................................. 65 
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`Cases
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`TABLE OF AUTHORITIES
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` IPR2016-00710
`Patent Owners’ Response
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` Page(s)
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`Allergan, Inc. v. Apotex Inc.,
`754 F.3d 952 (Fed. Cir. 2014) ............................................................................ 47
`
`Allergan, Inc. v. Sandoz Inc.,
`796 F.3d 1293 (Fed. Cir. 2015) .......................................................................... 46
`
`Amgen, Inc. v. AbbVie Biotechnology Ltd.,
`IPR2015-01514, Paper 9 (Jan. 14, 2015) ............................................................ 27
`
`Apotex Inc. v. Merck Sharpe & Dohme Corp.,
`IPR2015-00419, Paper 14 (June 25, 2015) ......................................................... 27
`
`Apple Inc. v. Samsung Electronics Co.,
`839 F.3d 1034 (Fed. Cir. 2016) (en banc) .......................................................... 63
`
`Arendi S.A.R.L. v. Apple Inc.,
`832 F.3d 1355 (Fed. Cir. 2016) .......................................................................... 44
`
`Crocs, Inc. v. International Trade Commission,
`598 F.3d 1294 (Fed. Cir. 2010) .......................................................................... 62
`
`InnoPharma Licensing, Inc. v. Senju Pharmaceutical Co.,
`IPR2015-00902, Paper 90 (July 28, 2016) ......................................................... 62
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`Institut Pasteur & Universite Pierre et Marie Curie v. Focarino,
`738 F.3d 1337 (Fed. Cir. 2013) .......................................................................... 64
`
`Kinetic Concepts, Inc. v. Smith & Nephew, Inc.,
`688 F.3d 1342 (Fed. Cir. 2012) .................................................................... 46, 65
`
`KSR International Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ............................................................................................ 47
`
`Ortho-McNeil Pharmaceutical, Inc. v. Mylan Laboratories, Inc.,
`520 F.3d 1358 (Fed. Cir. 2008) .......................................................................... 47
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`Patent Owners’ Response
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`Panduit Corp. v. Dennison Manufacturing Co.,
`810 F.2d 1561 (Fed. Cir. 1987) .......................................................................... 46
`
`Rolls-Royce, PLC v. United Technologies Corp.,
`603 F.3d 1325 (Fed. Cir. 2010) .................................................................... 48, 49
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`In re Rosuvastatin Calcium Patent Litigation,
`703 F.3d 511 (Fed. Cir. 2012) ............................................................................ 65
`
`Spectralytics, Inc. v. Cordis Corp.,
`649 F.3d 1336 (Fed. Cir. 2011) .......................................................................... 46
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`I.
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`INTRODUCTION
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`When U.S. Patent No. 6,331,415 (“the ’415 patent”) was filed in April 1983,
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`scientists were struggling to produce even a single antibody light chain using
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`recombinant technology, and no one had reported the successful expression of an
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`antibody heavy chain. Nobel laureates and other leading scientists had speculated
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`about the possibility of recombinantly producing an antibody (which has two light
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`chains and two heavy chains), but even they were uncertain whether and when that
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`goal might be achieved.
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`Faced with those uncertainties, the ’415 inventors not only demonstrated that
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`it was possible to produce a functional antibody recombinantly, but they did so in
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`an innovative way: by inserting the different genes encoding for the heavy and
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`light chains into a single host cell. Their invention is reflected in the challenged
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`claims, which recite a process for producing a functional antibody by expressing
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`the heavy and light chains “in a single host cell” (claims 1, 33) or “[a] transformed
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`host cell comprising at least two vectors” with each vector separately containing
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`the DNA encoding for either the heavy or light chain (claim 18).
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`The ’415 patent was a dramatic advance. As of April 1983, no one had
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`reported making any eukaryotic protein containing multiple different polypeptide
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`chains by inserting more than one gene into a single host cell. The ’415 inventors
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`not only made a functional antibody, but did so by adopting a single host cell
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`approach that had never been demonstrated to work even with much simpler
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`proteins.
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`Decades later, Mylan seeks to rewrite this history leading up to the ’415
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`patent by attributing its invention to others. But the primary reference underlying
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`both grounds, U.S. Patent No. 4,495,280 (“Bujard”) (Ex. 1002), does not disclose
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`co-expressing the genes encoding for antibody heavy and light chains in a single
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`host cell, as required by the challenged claims. Indeed, the Board itself previously
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`held that Bujard does not anticipate the challenged claims because it “does not
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`teach” that key limitation “either expressly or inherently.” (IPR2015-01624, Paper
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`15 at 15.)
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`Based on the record at the institution stage—including Dr. Jefferson Foote’s
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`then-untested declaration assertions—the Board concluded that Bujard “suggests”
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`the ’415 invention.1 The full record, including Dr. Foote’s own deposition
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`testimony, now leads to the opposite conclusion.
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`Bujard addressed how to construct expression vectors containing strong
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`bacterial promoters—a very different problem from the one addressed in the ’415
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`1
`Dr. Foote’s declaration was submitted in a prior proceeding (IPR2015-
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`01624), which Mylan sought to join. Mylan also relies on Dr. Foote’s declaration
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`in this proceeding. (Paper 2 at 3; Paper 13 at 6.)
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`patent. The only place Bujard even mentions antibodies is in a lengthy, generic list
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`of “proteins of interest,” and the record now shows that Bujard’s prosecuting
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`attorney simply recycled that list from several dozen prior, unrelated patent
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`applications.
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`The record now contains the testimony of Dr. John Fiddes (Ex. 2019)—a
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`molecular biologist with 40 years of experience—who, among other things,
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`explains that Bujard’s reference to a “multimer” does not refer to a multimeric
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`protein, as Dr. Foote suggested, and instead refers to multiple repeating copies of
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`the same gene.
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`The record also now contains the testimony of Dr. Reiner Gentz (Ex. 2021),
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`who worked in Dr. Bujard’s lab in the early 1980s and co-authored the scientific
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`paper corresponding to the Bujard patent. Dr. Gentz testified that he was not
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`aware of anyone in Dr. Bujard’s lab who used or mentioned co-expressing multiple
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`different eukaryotic genes in a single host cell, much less using that approach to
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`make an antibody.
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`Moreover, even Dr. Foote’s post-institution testimony supports the
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`patentability of the challenged claims. For example, Dr. Foote admitted at his
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`deposition that there were numerous challenges with producing antibodies
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`recombinantly as of April 1983, such that even leading antibody scientists doubted
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`whether it would ever be possible to produce recombinant antibodies. And Dr.
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`Foote further admitted that neither Bujard nor any of the other cited references
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`purports to solve those challenges.
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`Mylan also relies upon Dr. Kathryn Calame’s declaration. But Dr. Calame
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`merely adopted Dr. Foote’s declaration in its entirety without any further
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`elaboration of her own, and her deposition testimony confirms that her opinion is
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`not based on an objective assessment of the state of the art. Indeed, despite
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`extensive work as an expert attempting to invalidate the ’415 patent in a prior
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`litigation, Dr. Calame had not even read Bujard until after reviewing the ’415
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`patent and Dr. Foote’s declaration. And at the time of her deposition, Dr. Calame
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`still had not read or considered the significant evidence rebutting Dr. Foote’s
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`declaration opinions, including Dr. Foote’s deposition testimony, Dr. Fiddes’s
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`declaration in IPR2015-01624, or even the Board’s institution decision in
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`IPR2015-01624 that had rejected several of Dr. Foote’s opinions, which Dr.
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`Calame nevertheless adopted.
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`Bujard’s failure to show that recombinant techniques could be deployed to
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`make a functional antibody or that both antibody chains could be expressed in a
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`single host cell is dispositive of both instituted grounds. The combinations of
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`references in each ground do not cure Bujard’s shortcomings.
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`For Ground 1, Mylan relies upon Bujard combined with Riggs & Itakura
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`(Ex. 1003). But as the Board previously found, “Riggs & Itakura takes a different
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`approach than the ‘single host cell’ approach required by the claims.” (IPR2015-
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`01624, Paper 15 at 19.) Riggs & Itakura teaches a separate host cell for each
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`polypeptide chain—contrary to the single host cell approach of the challenged
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`claims. Moreover, nothing in Riggs & Itakura would have given a person of
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`ordinary skill any expectation of success in producing an antibody in a single host
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`cell, particularly given the state of the art and uncertainties at the time.
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`For Ground 2, Mylan relies upon Bujard combined with Southern (Ex. 1004)
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`to challenge certain claims that cover using two vectors in a single host cell. But
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`Southern does not disclose any experiment expressing two genes corresponding
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`with the different chains of a multi-unit protein in a single host cell, let alone
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`suggest that such a technique could be used with antibodies (which Southern never
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`mentions). And in any case, the techniques described in Bujard and Southern are
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`incompatible: Bujard relates to bacterial cells, whereas Southern describes a
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`mammalian expression vector. A person of ordinary skill thus would have had no
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`reason to combine them.
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`Finally, although not addressed in the institution decision or even considered
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`by Drs. Foote or Calame, the record also now includes strong objective evidence of
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`non-obviousness. The industry has embraced the validity of the ’415 patent, taking
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`dozens of licenses, amounting to well over a billion dollars in royalties. And the
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`commercial success of the many “blockbuster” products made by Genentech and
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`others using the ’415 invention cannot be disputed—Genentech alone has
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`generated over $100 billion in sales of products made with the ’415 invention.
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`Finally, at a time when leading scientists were skeptical that the many challenges
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`to producing an antibody recombinantly could be overcome, the ’415 inventors not
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`only succeeded, but did so in an unexpected way—by co-expressing antibody
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`heavy and light chains in a single host cell. This objective evidence weighs
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`heavily against a hindsight-based finding of obviousness.
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`Accordingly, Patent Owners respectfully request that the Board affirm the
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`patentability of the challenged claims.
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`II. TECHNOLOGY BACKGROUND
`A.
`Proteins Vary In Size And Complexity.
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`There are many different proteins, which vary in size and complexity.
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`Monomeric proteins consist of a single polypeptide chain, while multimeric
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`proteins consist of multiple polypeptide chains. (Ex. 2019, Fiddes Decl. ¶¶ 24-34.)
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`A simple example of a multimeric eukaryotic protein is insulin, which has an
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`A chain (21 amino acids) and a B chain (30 amino acids) linked by two disulfide
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`bonds (and a third intrachain bond):
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`(Id. ¶¶ 35-37; Ex. 2020, Foote Dep. 83, 116-18; Ex. 1003 at 532.)2
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`Antibodies (also called immunoglobulins) are larger and far more complex
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`than insulin. Antibodies play a critical role in the body’s immune system by
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`binding to foreign substances called “antigens” (e.g., bacteria, viruses), facilitating
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`removal of the antigen from the body. Each antibody consists of at least four
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`chains—typically, two identical heavy chains and two identical light chains
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`assembled into a “Y”-shape, held together by over a dozen disulfide bonds:
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`2
`“Eukaryotic” organisms have cells with a nuclear membrane and distinct
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`chromosomes containing their genetic material, which distinguishes them from
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`simpler “prokaryotic” organisms (e.g., bacteria). (Ex. 2018 at 11-12, 15-20, Table
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`1-1.)
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`(Ex. 1001, 3:17-26, Fig. 1; Ex. 2019, Fiddes Decl. ¶¶ 38-42; Ex. 2020, Foote Dep.
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`86.) The molecular models below illustrate the larger size and complexity of an
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`antibody (right) as compared to insulin (left):
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`(Ex. 2019, Fiddes Decl. ¶¶ 43-45.) An antibody of the immunoglobulin G (“IgG”)
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`isotype contains more than 1,300 amino acids and has a molecular weight of about
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`150,000 Daltons, while insulin contains only 51 amino acids and weighs just 5,800
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`Daltons. (Id. ¶¶ 39-44; Ex. 2020, Foote Dep. 105-06.)
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`B.
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`Prior Art Antibody Production Techniques
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`For decades before the ’415 patent, antibodies could be produced by
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`immunizing an animal (e.g., a mouse) with an antigen, generating a polyclonal
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`mixture of antibodies with different binding characteristics. By April 1983,
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`polyclonal antibodies were widely used. (Ex. 1001, 1:45-63; Ex. 2019, Fiddes
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`Decl. ¶¶ 46-47.)
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`But many diagnostic and therapeutic applications will not work with
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`polyclonal antibodies, and instead require compositions that contain only one type
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`of antibody with uniform binding characteristics, called “monoclonal” antibodies.
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`(Ex. 1001, 1:45-2:11; Ex. 2019, Fiddes Decl. ¶¶ 46-50.) Before the ’415 invention,
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`such monoclonal antibodies were produced using “hybridomas” (developed in
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`1975 by Dr. César Milstein),3 which fuse an antibody-producing B cell with a
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`cancer cell. (Ex. 2019, Fiddes Decl. ¶¶ 48-50.) By April 1983, hybridomas were
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`being used extensively to produce monoclonal antibodies, and these uses were
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`“expanding very rapidly.” (Ex. 1039, Milstein at 407; Ex. 2019, Fiddes Decl. ¶ 50;
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`3
`Dr. Milstein won the Nobel Prize for this work.
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`Ex. 2020, Foote Dep. 37, 48-49 (hybridomas were a “[v]ery big” deal in the early
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`1980s due to “significant achievements”); Ex. 1001, 1:64-2:11.)
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`C. By April 1983, Recombinant Techniques Were Not Well
`Understood And Had Only Been Used To Make Simple Proteins.
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`Recombinant techniques allow scientists to introduce a new gene into a host
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`cell that does not naturally contain that gene, and then to produce a desired protein
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`from the inserted gene. (Ex. 2019, Fiddes Decl. ¶¶ 51-56.)
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`In April 1983, many of the biological mechanisms controlling the expression
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`of foreign DNA and assembly of the resulting proteins were poorly understood.
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`For example, Dr. Timothy Harris published an article in April 1983 explaining:
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`“[I]t is clear that not all the rules governing the expression of cloned genes have
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`been elaborated and those rules that do exist are still largely empirical.” (Ex. 1027,
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`Harris at 129; Ex. 2020, Foote Dep. 135; Ex. 2010, Calame Dep. 233-34; Ex. 2019,
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`Fiddes Decl. ¶ 57.)
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`Only a few relatively small and simple proteins had been recombinantly-
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`produced by April 1983—as reflected in Harris’s Table 2, which provided “an up
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`to date summary of the higher eukaryotic proteins that have been expressed in E.
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`coli.” (Ex. 1027, Harris at 163-69, Table 2; Ex. 2068, Harris Decl. ¶ 16
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`(describing listed proteins as “relatively small polypeptides with simple tertiary
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`structures”); Ex. 2020, Foote Dep. 76-79; Ex. 2019, Fiddes Decl. ¶ 57.)
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`Harris identified several perceived problems as of April 1983 with
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`producing eukaryotic proteins recombinantly in prokaryotic hosts, such as (1) the
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`presence of introns (non-coding sequences) in eukaryotic genes; (2) the different
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`regulatory signals found in eukaryotic DNA; (3) the different codon usage in
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`eukaryotic genes; and (4) factors “not well defined” affecting protein folding,
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`solubility, and post-translational modifications. (Ex. 1027, Harris at 131-33, 156,
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`173.) Those perceived challenges explain why the only reported recombinantly-
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`produced eukaryotic proteins at that time were relatively simple. (Ex. 2019, Fiddes
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`Decl. ¶¶ 58-80.) At his deposition, Dr. Foote agreed with Harris’s summary of the
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`many challenges that existed with recombinant DNA techniques as of April 1983.
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`(Ex. 2020, Foote Dep. 136-46.)
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`The prospect of using recombinant DNA to produce a multimeric protein
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`was especially challenging. By April 1983, only one multimeric eukaryotic protein
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`(insulin) produced from two different genes had been made recombinantly. That
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`work with insulin involved either producing preproinsulin (a single polypeptide),
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`or separately expressing the A and B chains in two different host cells and joining
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`the subunits afterward. (Ex. 2019, Fiddes Decl. ¶¶ 81-91; Ex. 2020, Foote Dep.
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`103, 109-11; Ex. 2007, Harris Decl. II ¶ 14; Ex. 2010, Calame Dep. 120-21.)
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`Just like insulin, every other eukaryotic protein reported in the literature
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`before April 1983 was made using one host cell per polypeptide chain. (Ex. 2019,
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`Fiddes Decl. ¶¶ 127-28.) Indeed, even Drs. Foote and Calame admitted at their
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`respective depositions that the record is devoid of evidence that anyone had co-
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`expressed the different subunits of any multimeric eukaryotic protein in the same
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`host cell before the ’415 inventors. (Ex. 2020, Foote Dep. 114-15; id. at 111-12
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`(all of Harris’s examples “involved production of one polypeptide in one
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`transformed host cell”); Ex. 2010, Calame Dep. 204, 230 (confirming no proteins
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`identified in Dr. Foote’s declaration or Harris were produced by co-expressing
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`different polypeptide chains in a single host cell).) Testimony from multiple
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`persons of extraordinary skill in other proceedings involving the ’415 patent
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`confirms that conclusion; all were unaware of anyone who had independently
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`expressed the multiple different subunits of a eukaryotic protein in a single host
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`cell before April 1983. (Ex. 2007, Harris Decl. II ¶¶ 15-16; Ex. 2041, McKnight
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`Decl. II ¶ 5; Ex. 2080, Rice Decl. ¶ 15.)
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`At her deposition, Dr. Calame noted that Harris’s list included proteins that
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`contain multiple chains of the same polypeptide encoded by a single gene, such as
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`influenza HA. (Ex. 2010, Calame Dep. 222-28.) But that only underscores the
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`absence of any multimeric eukaryotic protein containing polypeptide chains
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`encoded by different genes—such as an antibody. (Ex. 2019, Fiddes Decl. ¶ 80.)
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`Proteins like influenza HA were made using the same one-polypeptide-per-host-
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`cell approach as every other eukaryotic protein before April 1983. (Id.)
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`It is not surprising that no one as of April 1983 had reported producing more
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`than one polypeptide of a eukaryotic multimeric protein in a single host cell. Co-
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`expressing multiple different polypeptides in a single host cell is far more
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`complicated than the prior art approach that used multiple host cells. For example,
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`before April 1983, it would have been (i) more difficult to engineer expression
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`constructs for use in a single host cell; (ii) uncertain that separate genes of interest
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`would even co-express; and (iii) unclear whether the desired polypeptides would
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`be produced in the correct ratios, or whether that was even necessary. (Ex. 2019,
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`Fiddes Decl. ¶¶ 129-37; Ex. 2021, Gentz Decl. ¶¶ 27-30.)
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`D. As Of April 1983, Leading Scientists Were Uncertain Whether It
`Was Possible To Make Antibodies Recombinantly.
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`By the early 1980s, a handful of scientists had begun to theorize that it might
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`be possible in the future to produce antibodies recombinantly. But the
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`uncertainties with producing antibodies recombinantly were even greater than with
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`other proteins—for example, some scientists believed antibodies required special
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`“helper” proteins to coordinate the expression and proper assembly of heavy and
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`light chains. (Ex. 2019, Fiddes Decl. ¶¶ 95, 136.) As such, even by April 1983,
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`highly-respected scientists still had serious doubts whether antibodies could ever
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`be produced recombinantly, and nobody had suggested that antibodies could be
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`produced by co-expressing the heavy and light chains in a single host cell.
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`For example, in March 1981, an article reported then-recent comments from
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`Dr. Milstein—inventor of the hybridoma technique, future Nobel laureate, and
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`prominent antibody scientist. In his closing remarks, Dr. Milstein speculated about
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`the future—noting he could “imagine the next stage is to move away from the
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`animals,” and that it was “perhaps not too premature to start thinking along these
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`lines.”4 (Ex. 1039, Milstein at 409.) He did not offer any solution; rather, he just
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`said that “[s]omehow the DNA fragments will have to go into cells capable of
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`transcribing and translating the information with adequate efficiency.” (Id. at 409-
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`10; Ex. 2020, Foote Dep. 47-61 (agreeing Milstein’s comments are “directed
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`towards possible things that might be done in the future”); Ex. 2019, Fiddes Decl.
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`¶¶ 102-03.)
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`In fact, Dr. Milstein conceded that his wishful idea might not work: “[W]e
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`have to face the possibility that bacteria may not be able to handle properly the
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`separated heavy and light chains so that correct assembly becomes possible.” (Ex.
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`1039, Milstein at 410.) He explained that the basic science presented “very serious
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`problems,” was “not so well established,” and was “clouded by uncertainties and
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`multiple possibilities.” (Id.; Ex. 2020, Foote Dep. 55-61; Ex. 2019, Fiddes Decl.
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`¶¶ 102-07.)
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`4
`All emphases added unless otherwise indicated.
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`The years leading up to the ’415 patent confirmed the many problems
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`forecast by Dr. Milstein. During that period, leading antibody scientists
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`encountered numerous uncertainties and unexplained results while attempting to
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`recombinantly express just a single antibody chain:
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` In 1982, Falkner & Zachau could not explain why they had failed to
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`express antibody light chain, speculating that “something may be missing
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`from our systems” or “some as yet undefined factors provided in tissue-
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`specific differentiation events may have a role.” (Ex. 2022 at 288.)
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` In December 1982, Dr. David Baltimore, a Nobel laureate, observed that
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`“relatively little is known about the molecular mechanisms that control
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`[antibody] gene expression.” (Ex. 1020 at 7862.)
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` In February 1983, Oi et al. could not explain why two cell lines failed to
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`produce any detectable light chain from recombinant DNA. (Ex. 1031 at
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`827-28.)
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` In March 1983, Ochi et al. reported introducing the gene encoding for
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`antibody light chain into cells already producing heavy chains, and could
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`not explain why nearly all cell lines had no detectable antibody
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`production or the observed “variability in gene expression.” (Ex. 1021 at
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`341-42.)
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`(Ex. 2019, Fiddes Decl. ¶¶ 108-20.) Consistent with this evidence, Dr. Calame’s
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`literature search failed to identify anyone who successfully expressed a complete
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`antibody heavy chain from recombinant DNA prior to April 1983. (Ex. 2010,
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`Calame Dep. 74.)
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`This uncertainty and unpredictability continued through April 1983. Indeed,
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`even Sir Gregory Winter—a world-leading antibody scientist—confirmed that he
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`was “uncertain in the spring of 1983 about how to express recombinant
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`antibodies,” and that he still believed at the time that any solution “would be a
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`major undertaking without any certainty of success.” (Ex. 2023, Winter Rep. ¶ 61;
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`Ex. 2019, Fiddes Decl. ¶¶ 122-26.) Dr. Foote testified that he has no basis to
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`disagree with that description of the uncertainty in the art (Ex. 2020, Foote Dep.
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`178-80), or with Dr. Winter’s similar statements that:
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` “[T]he field of heterologous protein expression (the expression of a
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`protein in cells that do not normally express the protein) was an
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`emerging and unpredictable field in April 1983.” (Ex. 2023, Winter
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`Rep. ¶ 31; Ex. 2020, Foote Dep. 173; Ex. 2019, Fiddes Decl. ¶¶ 123,
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`126.)
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` “[T]he reasons for success or failure in the expression or secretion of the
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`light chain in different cell types [in Falkner, Oi, Ochi, and Rice] were
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`not clear,” and as of April 1983 “there were no publications describing
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`the expression of recombinant antibody heavy chains in mammalian
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`cells.” (Ex. 2023, Winter Rep. ¶¶ 56-57; Ex. 2020, Foote Dep. 174-77.)
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` “[He] was sufficiently uncertain in the spring of 1983 about how to
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`express recombinant antibodies, and in sufficient yield, that [he]
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`postponed [his] proposed project to engineer the functional sites of
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`antibodies.” (Ex. 2